Analyzing Infectious Complications With DMARDs: A Comparative Study

Low dose methotrexate more likely to cause infectious adverse events than higher doses of the same drug.

In a 2015 study published in the March-April edition of the journal Clinical Experimental Rheumatology, researchers Lampropoulos and colleagues investigated the effect of disease-modifying antirheumatic drugs (DMARDs) on patients with rheumatoid arthritis (RA) in terms of treatment-related adverse events.

Among DMARDs available today for RA, targeted synthetic oral agents, biologic injectable agents, and traditional DMARDs are available. All of these treatments are known to have infectious complications, with varying incidence and severity. Treatments have this side effect in common due to the common treatment mechanism: inhibition of the exaggerated immune response in RA.

Of 1043 adults receiving biologic and synthetic DMARDs, 969 patients received synthetic biologic agents and the remaining 434 patients received synthetic agents. On both Kaplan-Meier and Cox proportional hazards statistical estimates of infectious adverse event rates, the risk of infectious complications was significantly higher in patients receiving biologic agents than in patients receiving synthetic agents. In fact, the risk was nearly twice as high, with a hazard ratio of 1.90, and a 95% confidence interval indicating a 64% to 139% increase in the risk of infectious events among users of biologics.

Unexpectedly, researchers found that low doses (ie, 10 mg or lower) of the traditional but widely used synthetic oral agent methotrexate were more likely to cause infectious adverse events than higher doses of the same drug.

This study has potential clinical implications for patients initiating treatment for RA. For instance, patients who are concerned about the potential infectious complications of treatment may opt for treatment with oral synthetic agents before attempting injectable biologic therapy.

Among the synthetic agents available for RA today, only 1—tofacitinib, or Xeljanz—is consired a true targeted synthetic agent. This distinction belongs to Xeljanz primarily because the treatment was designed with a targeted mechanism in mind—inhibition of the Janus Kinase pathway.

Some commentators have viewed this as an artificial distinction given that other medications for RA, such as leflunomide (Arava), are targeted treatments (ie, inhibiting dihydroorotate reductase), but are targeted by chance, not having been designed specifically to inhibit this enzyme.

Targeted therapies continue to have an important role in treatment of RA. However, selection of treatments based on the risks and benefits of therapy is an important consideration. With more comparative studies offering data about these risks and benefits in patients with RA, rheumatologists and patients with RA will have more data to make informed choices about appropriate options for initial therapy.

Reference

• Lampropoulos CE, Orfanos P, Bournia VK, et al. Adverse events and infections in patients with rheumatoid arthritis treated with conventional drugs or biologic agents: a real world study. Clin Exp Rheumatol. 2015;33(2):216-224.
• Smolen JS, van der Heijde D, Machold KP, Aletaha D, Landewé R. Proposal for a new nomenclature of disease-modifying antirheumatic drugs. Ann Rheum Dis. 2014;73(1):3-5.